DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of the Claims
Claims 1, 3, 5, 7, 10-16, and 29-30 are pending.
Claims 1, 3, and 7 are newly amended.
Claim 30 is newly added.
Claims 1, 3, 5, 7, 10-16, and 29-30 have been examined on their merits.
Withdrawn Objections & Rejections
The objections and rejections presented herein represent the full set of objections and rejections currently pending in the application. Any objections or rejections not specifically reiterated are hereby withdrawn.
The rejection of the claims is maintained but modified to address the amendments and new claim as discussed below.
Claim Interpretation
Claim 1 is limited to “de-differentiated fibroblasts.” While the specification states, “In some embodiments, passaged cells are defined as ‘dedifferentiated’ if expression of OCT-4 is detected” (paragraph [0116]), the disclosure does not specifically define what a de-differentiated fibroblast is.
As evidenced by Merriam-Webster (retrieved from internet 10/23/2024, previously cited), “dedifferentiation” means “reversion of a specialized structure (such as cells) to a more generalized or primitive conditions often as a preliminary physiological or structural change”.
Therefore, giving the term its broadest reasonable interpretation in view of the disclosure and the art, “de-differentiated fibroblasts” have been interpreted as any fibroblast-derived cell that has reverted to a more generalized or primitive condition, including any fibroblast-derived cell that expresses OCT-4.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 3, 5, 10, and 13-16 are rejected under 35 U.S.C. 103 as being unpatentable over Lim et al. (US 20160220613 A1, on IDS 11/04/2020, previously cited) in view of Lai et al. (Scientific Reports, 2017, on IDS 07/05/2022, previously cited), Mathieu et al. (Cell Stem Cell, 2015, previously cited) and Anokye-Danso et al. (Cell Stem Cell, 2011, previously cited).
In regards to claims 1, 5, 10, and 13-14, Lim teaches a method for repairing cell homeostasis or treating an individual suffering from a disease or tissue injury with exosomes derived from MSCs (claims 10 and 12) that can specifically be used to treat intervertebral disc degeneration (paragraph [0077]). Lim teaches that the exosomes may be contained within a composition that may be conditioned media that may be used as a therapy (paragraphs [0173-0177, and 0282]).
In regards to a “de-differentiated fibroblast”, while, as taught by Lai, MSCs express OCT-4 (p7, third paragraph), Lim does not explicitly teach that the MSCs derived from fibroblasts specifically.
However, methods for “de-differentiating” MSCs from fibroblasts are known in the art.
In particular, Lai teaches a method for the efficient generation of induced Oct-4 expressing MSCs from human dermal fibroblasts, which is achieved by adding a cocktail of chemical inhibitors in culture without reprogramming media comprising transcription factors (Title, Abstract, p1; Discussion, p4; Figure 1, p3). Lai also teaches that MSCs are used in hundreds of clinical trials for disease treatments; have much higher clonogenicity compared to fibroblasts; can be passaged multiple times; and can be further differentiated into osteoblasts, adipocytes, and chondrocytes (Abstract, p1).
A person of ordinary skill in the arts would have been motivated to use de-differentiated fibroblasts because it could provide an alternate source of MSCs for when obtaining them from blood is not possible or practical, and do so in a way that would be less invasive for patients. Furthermore, because Lai teaches explicit methods for de-differentiating cells (MSCs) from fibroblasts without reprogramming media comprising transcription factors (Discussion, p4; Generation of iMSCs, p9); advocates for their use in therapeutic application (p9, last paragraph of Discussion); and Lim and Lai are in the same technical field of deriving MSCs for clinical application, it could have been done with predictable results and a reasonable expectation of success.
Lim as modified by Lai is silent as to the oxygen conditions of the de-differentiating cells.
However, a person of ordinary skill in the arts would have been motivated to de-differentiate fibroblasts in hypoxic conditions because Mathieu teaches that pluripotent stem cells (OCT-4 expressing cells) have distinct metabolic requirements, and reprogramming cells to pluripotency requires a shift from oxidative to glycolytic metabolism (Summary, p592). Moreover, in particular, Mathieu teaches that reprogramming is significantly more efficient under hypoxic (2% and 5%, which lies within the ranges as in claim 13) conditions (Reprogramming process has hypoxic expression signature, p593). Furthermore, because Mathieu teaches methods for reprogramming fibroblasts under hypoxic (2% and 5%) conditions (Reprogramming process has hypoxic expression signature, p593; Cell culture and reprogramming, p602); and Lim, Lai, and Mathieu are in the same technical field of utilizing OCT-4 positive cells, it could have been done with predictable results and a reasonable expectation of success.
Lim as modified by Lau and Mathieu does not explicitly teach a step of de-differentiating fibroblasts by exposure to valproic acid (VPA).
However, a person of ordinary skill in the arts would have been motivated to de-differentiate fibroblasts with VPA because Anokye-Danso teaches that VPA is required for reprogramming fibroblasts by specifically degrading Hdac2 which allows for highly efficient reprogramming without expression of other known reprogramming factors (Introduction, p376). Furthermore, because Anokye-Danso teaches method for reprogramming fibroblasts with VPA (Figure 1, p377), and Lai, Lim, Mathieu, and Anokye-Danso are in the same technical field of utilizing OCT-4 positive cells, it could have been done with predictable results and a reasonable expectation of success.
In regards to claim 3, Lim teaches that the exosomes express at least markers CD9 and CD63 (paragraph [0181]).
In regards to claim 15, Lim teaches that the exosomes may be purified by ion (of which an anion is a type) exchange chromatography (paragraph [0284]).
In regards to claim 16, Lim teaches that mesenchymal stem cells may be administered to an individual (paragraph [0331]). Lim also teaches that the use of bone marrow to treat disease is known in the art (paragraph [0106]). Therefore, a person of ordinary skill in the arts would have been motivated to use BM-MSCs because they are common in the art, and because Lim teaches both that MSCs and bone marrow can be administered to patients, it could have been done with predictable results and a reasonable expectation of success.
Therefore, the combined teachings of Lim, Lai, Mathieu, and Anokye-Danso render the invention unpatentable as claimed.
Claims 7 and 30 are rejected under 35 U.S.C. 103 as being unpatentable over Lim et al. (US 20160220613 A1, on IDS 11/04/2020, previously cited) in view of Lai et al. (Scientific Reports, 2017, on IDS 07/05/2022, previously cited), Mathieu et al. (Cell Stem Cell, 2015, previously cited) and Anokye-Danso et al. (Cell Stem Cell, 2011, previously cited), as applied to claim 1, and further in view of Collas et al. (Reproductive BioMedicine Online, 2006, previously cited).
In regards to claims 7 and 30, Lim as modified by Lai and Mathieu, does not explicitly teach that the de-differentiated fibroblasts were produced upon exposure to stem cells.
However, Collas teaches that while functional reprogramming of differentiated cells pluripotency may present beneficial applications in regenerative medicine, and while somatic cell nuclear transfer may offer this possibility, technical hurdles and ethical guidelines currently prevent application of this technology (Abstract, p762). Therefore, Collas teaches a method that includes the fusion of different cells with embryonic stem cells to reprogram differentiated cells into multipotent or pluripotent cells (Abstract, p762). Therefore, a person of ordinary skill in the arts would have been motivated to “de-differentiate” somatic cells such as fibroblast by exposure to stem cells, such as embryonic stem cells, because it would provide an alternative means of establishing pluripotent cells which can then be used for therapeutic application while overcoming the technical and ethical limitations of other methods. Furthermore, because Collas teaches method for inducing pluripotency by contacting cells with embryonic cells (Epigenetic reprogramming and induction of pluripotency by cell fusion, p763) and teaches that this is a known technique in the art over a variety of cells types (Introduction, p762), it could have been done with predictable results and a reasonable expectation of success.
Therefore, the combined teachings of Lim, Lai, Mathieu, Anokye-Danso, and Collas render the invention unpatentable as claimed.
Claims 11-12 are rejected under 35 U.S.C. 103 as being unpatentable over Lim et al. (US 20160220613 A1, on IDS 11/04/2020, previously cited) in view of Lai et al. (Scientific Reports, 2017, on IDS 07/05/2022, previously cited), Mathieu et al. (Cell Stem Cell, 2015, previously cited) and Anokye-Danso et al. (Cell Stem Cell, 2011, previously cited), as applied to claim 1 above, and further in view of Jung et al. (ACS Chemical Biology, 2014, previously cited).
In regards to claims 11-12, Lim as modified by Lai and Mathieu, does not explicitly teach that the de-differentiated fibroblasts were produced upon exposure to one or more DNA methyltransferase inhibitors.
However, a person of ordinary skill in the arts would have been motivated to de-differentiate fibroblasts in conditions with a DNA methyltransferase inhibitor such as decitabine because Jung teaches that decitabine is a well-characterized DNA methyltransferase inhibitor, that can improve reprogramming efficiency; allow for reprogramming without the need for the factor c-Myc which is known to be oncogenic; and facilitate erasure of epigenetic memory and reduce DNA hypermethylation (DNA methyltransferases (DNMTs), p87). Furthermore, because Jung teaches that the use of decitabine is well characterized and points to methods for using decitabine to reprogram fibroblasts (DNA methyltransferases (DNMTs), p87), it could have been done with predictable results and a reasonable expectation of success.
Therefore, the combined teachings of Lim, Lai, Mathieu, Anokye-Danso, and Jung render the invention unpatentable as claimed.
Claim 29 is rejected under 35 U.S.C. 103 as being unpatentable over Lim et al. (US 20160220613 A1, on IDS 11/04/2020, previously cited) in view of Lai et al. (Scientific Reports, 2017, on IDS 07/05/2022, previously cited), Mathieu et al. (Cell Stem Cell, 2015, previously cited) and Anokye-Danso et al. (Cell Stem Cell, 2011, previously cited), as applied to claims 1 and 3 above, and further in view of Erwin et al. (WO2010088775A1, 2010) and Bach et al. (Oncotarget, 2017).
In regards to claim 29, Lim does not explicitly teach that the exosomes express the marker CD56 (which is the same as NCAM).
However, as taught by Erwin, notochordal conditioned media, comprises soluble factors secreted by NCAM (CD56)-positive notochordal cells cultured under hypoxic conditions (paragraphs [0038-0041, 00296]). Continuing, Erwin teaches that this media is useful for treating degenerative disc disease in patients (paragraph [0017]). As taught by Bach, extracellular vesicles (of which exosomes are a type) found in notochordal conditioned media exert regenerative effects on nucleus pulposus cells in the intervertebral disc (Abstract, p88845).
Therefore, a person of ordinary skill in the art would have been motivated to include CD56-positive exosomes because they would promote regeneration of nucleus pulposus cells in the intervertebral disc. Furthermore, because Erwin teaches that degenerative disc diseases may be treated with conditioned media comprising CD56/NCAM (claims 19, 43) and because Bach teaches that vesicles derived from notochordal conditioned media exert regenerative effects on nucleus pulposus cells in the intervertebral disc, it could have been done with predictable results and a reasonable expectation of success.
Therefore, the combined teachings of Lim, Lai, Mathieu, Anokye-Danso, Erwin, and Bach render the invention unpatentable as claimed.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 3, 5, 7, 10-11, 13-14, 16, and 30 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of copending Application No. 18/736,046 in view of Cheng et al. (Journal of Cellular and Molecular Medicine, first published 08/14/2017, on IDS 07/05/2022, previously cited).
Claim 12 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of copending Application No. 18/736,046 in view of Cheng et al. (Journal of Cellular and Molecular Medicine, first published 08/14/2017, on IDS 07/05/2022, previously cited), as applied to claims 1 and 11 above, and further in view of Jung et al. (ACS Chemical Biology, 2014, previously cited).
Claim 15 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of copending Application No. 18/736,046 in view of Cheng et al. (Journal of Cellular and Molecular Medicine, first published 08/14/2017, on IDS 07/05/2022, previously cited), as applied to claims 1 and 14 above, and further in view of Lim et al. (US 20160220613 A1, on IDS 11/04/2020, previously cited).
Claim 29 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of copending Application No. 18/736,046 in view of Cheng et al. (Journal of Cellular and Molecular Medicine, first published 08/14/2017, on IDS 07/05/2022, previously cited), as applied to claims 1 and 3 above, and further in view of Erwin et al. (WO2010088775A1, 2010) and Bach et al. (Oncotarget, 2017).
Although the claims at issue are not identical, they are not patently distinct from each other because both inventions are drawn to methods for treating disc degeneration in patients which requires a step of exposing fibroblasts to valproic acid and hypoxic conditions (0.1-20% which overlaps with at least 2%-8%) (thus, de-differentiating fibroblasts). Both inventions require steps of administering de-differentiated fibroblasts.
While copending Application No. 18/736,046 does not require a step of providing conditioned media comprising exosomes from the de-differentiated fibroblasts to a patient, a person of ordinary skill in the art would have been motivated to provide conditioned media comprising exosomes from the de-differentiated fibroblasts to a patient because Cheng specifically teaches that exosomes in conditioned media from MSCs (which can be “de-differentiated fibroblasts”, as discussed above) inhibit nucleus pulposus cell apoptosis and alleviate interverbal disc degeneration (Abstract, p261; Exosome characterization, Exosomes uptake by NPCs, p263). Cheng also teaches that these exosomes are CD63 positive (Exosome characterization, p263).
Furthermore, because Cheng teaches that patients could be effectively treated with MSC-exosomes, and that this reduced cell apoptosis and disc degeneration (Intradiscal injection of MSC-exosomes alleviated the NPC apoptosis and IVD degeneration in a rat model, p271), it could have been done with predictable results and a reasonable expectation of success. This is a provisional nonstatutory double patenting rejection.
In regards to claim 12, while Copending Application No. 18/736,046 also teaches steps of exposing cells to a DNA methyl transferase inhibitor (claim 4) but is silent as to the specific inhibitor.
However, a person of ordinary skill in the arts would have been motivated to de-differentiate fibroblasts in conditions with a DNA methyltransferase inhibitor such as decitabine because Jung teaches that decitabine is a well-characterized DNA methyltransferase inhibitor, that can improve reprogramming efficiency; allow for reprogramming without the need for the factor c-Myc which is known to be oncogenic; and facilitate erasure of epigenetic memory and reduce DNA hypermethylation (DNA methyltransferases (DNMTs), p87). Furthermore, because Jung teaches that the use of decitabine is well characterized and points to methods for using decitabine to reprogram fibroblasts (DNA methyltransferases (DNMTs), p87), it could have been done with predictable results and a reasonable expectation of success.
In regards to claim 15, while Copending Application No. 18/736,046 does not explicitly teach a step of isolating exosomes by anion exchange chromatography, it would have been predictably obvious to use this technique because Lim teaches that the exosomes may be purified by ion (of which an anion is a type) exchange chromatography (paragraph [0284]).
In regards to claim 29, while Copending Application No. 18/736,046 does not explicitly require exosomes that express the marker CD56, as taught by Erwin, notochordal conditioned media, comprises soluble factors secreted by NCAM (CD56)-positive notochordal cells cultured under hypoxic conditions (paragraphs [0038-0041, 00296]). Continuing, Erwin teaches that this media is useful for treating degenerative disc disease in patients (paragraph [0017]). As taught by Bach, extracellular vesicles (of which exosomes are a type) found in notochordal conditioned media exert regenerative effects on nucleus pulposus cells in the intervertebral disc (Abstract, p88845).
Therefore, a person of ordinary skill in the art would have been motivated to include CD56-positive exosomes because they would promote regeneration of nucleus pulposus cells in the intervertebral disc. Furthermore, because Erwin teaches that degenerative disc diseases may be treated with conditioned media comprising CD56/NCAM (claims 19, 43) and because Bach teaches that vesicles derived from notochordal conditioned media exert regenerative effects on nucleus pulposus cells in the intervertebral disc, it could have been done with predictable results and a reasonable expectation of success.
Response to Arguments
Applicant argues that the specification demonstrates that de-differentiated fibroblasts exposed to the synergistic combination as in claim 1 provides better inhibition of TNF-alpha induced apoptosis and inhibition of stimulated NP cell proliferation than exosomes from undifferentiated fibroblasts and exosomes from fetal calf serum (citing Figs. 1 and 2; Remarks, p4-5).
Applicant's arguments filed 07/21/2026 have been fully considered but they are not persuasive.
In regards to Applicant’s allegations of unexpected results, whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the “objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support.” In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980) (see MPEP 716.02(d)).
In the instant case, the claims do not require any specific result regarding inhibition of TNF-alpha induced apoptosis (Fig. 1) or inhibition of stimulated NP cell proliferation (Fig. 2).
Furthermore, the claimed evidence only compares exosomes of generic “de-differentiated fibroblasts” (which is a broad term for any fibroblast-derived cell that has reverted to a more generalized or primitive condition, including any OCT-4 expressing cell derived from a fibroblast, and which can include stem cells) to fibroblasts, not other “de-differentiated fibroblast” subtypes (such as stem cells).
Additionally, as discussed above, as taught by Lim is was known in the art before the effective filing date that exosomes from stem cells could be used to treat disc degeneration.
Moreover, as evidenced by Cheng et al. (Journal of Cellular and Molecular Medicine, first published 08/14/2017, on IDS 07/05/2022, previously cited, see above in double-patenting rejection), it was known in the art that exosomes secreted from MSCs promote inhibition of TNF-α induced nucleus pulposus cell apoptosis and alleviate intervertebral disc degeneration (Results, p265-270; Fig. 2, p267; Fig. 6, p272-273).
Thus, these were the expected results of cells of cells with primitive characteristics (e.g., expression of pluripotency marker OCT4, such as “dedifferentiated fibroblasts) compared to differentiated fibroblasts.
Applicant also argues that the 132 Declaration previously submitted in co-pending Application no. 18/345,022 (which is noted is a DIV of the instant application) shows that exosomes from fibroblasts that have been de-differentiated with VPA and under hypoxic conditions (VH+ conditions) show more than two-fold increase in promoting regeneration of HUVECs and demonstrates unexpectedly superior results of the exosomes produced without VPA and hypoxia (Remarks, p5).
Applicant's arguments filed 07/21/2026 have been fully considered but they are not persuasive.
In regards to the 132 Declaration previously submitted (04/09/2026) in co-pending Application no. 18/345,022 which is noted is a DIV of the instant application), this declaration has not been submitted for consideration in the instant Application. Therefore, if Applicant wishes this declaration considered it should be submitted and made of record in the instant Application.
However, it is also noted that the results in the 132 Declaration previously submitted (04/09/2026) in co-pending Application no. 18/345,022 only discuss the effects of exosomes from VH+ de-differentiated fibroblasts on HUVEC proliferation or MHC 1 expression in comparison to OCT-4 reprogrammed de-differentiated fibroblasts. This is not only not commensurate in scope with the instant claims, which not only requires no effect, but also not germane to a method of treating disc degeneration as instantly claimed. Moreover, the cells in Application no. 18/345,022 explicitly “do not express MHC 1”. However, in the instant claims, the cells can express this marker (see claim 3). Therefore, the cells are different in these applications.
Applicant argues that showings of unexpected results need not include a limitation towards such unexpected results (Remarks, p5-6).
Citing MPEP 716.02(d), Applicant argues, “Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980) (Claims were directed to a process for removing corrosion at "elevated temperatures" using a certain ion exchange resin (with the exception of claim 8 which recited a temperature in excess of 100°C). Appellant demonstrated unexpected results via comparative tests with the prior art ion exchange resin at 110°C and 130°C. The court affirmed the rejection of claims 1-7 and 9-10 because the term "elevated temperatures" encompassed temperatures as low as 60°C where the prior art ion exchange resin was known to perform well. The rejection of claim 8, directed to a temperature in excess of 100°C, was reversed.). See also In re Peterson, 315 F.3d 1325, 1329-31, 65 USPQ2d 1379, 1382-85 (Fed. Cir. 2003) (data showing improved alloy strength with the addition of 2% rhenium did not evidence unexpected results for the entire claimed range of about 1-3% rhenium); In re Grasselli, 713 F.2d 731, 741, 218 USPQ 769, 777 (Fed. Cir. 1983) (Claims were directed to certain catalysts containing an alkali metal. Evidence presented to rebut an obviousness rejection compared catalysts containing sodium with the prior art. The court held this evidence insufficient to rebut the prima facie case because experiments limited to sodium were not commensurate in scope with the claims.).”
In particular, Applicant emphases the line “The rejection of claim 8, directed to a temperature in excess of 100°C, was reversed” and asserts that the claims do not need to include a recitation of unexpected results because the scope of the claims is commensurate in scope with the showing in the examples of the specification and the declaration (Remarks, p6).
Applicant argues that both examples in the specification and in the Declaration show 1) fibroblasts dedifferentiated using VPA and hypoxia and 2) exosomes from such fibroblasts provided to mice as a method of treating disc degeneration (Remarks, p6).
Applicant further argues that the declaration specifically shows superior results when dedifferentiation is achieved with VPA and hypoxic conditions (Remarks, p6).
Applicant's arguments filed 07/21/2026 have been fully considered but they are not persuasive.
As noted by Applicant, MPEP 716.02(d), whether unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the “objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support.” In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980).
Moreover, in regards to In re Clemens, the rejection of claim 8 was overturned specifically because, as cited by Applicant, “The rejection of claim 8, directed to a temperature in excess of 100°C, was reversed” (emphasis added).
This is in contrast to the rejection of 1-7 and 9-10 where the term “elevated temperatures” encompassed temperatures as low as 60°C where the prior art ion exchange resin was known to perform well.
Thus, in Clemens, claim 8 was reversed not because of demonstrations of unexpected results not recited in the claims as argued by Applicant, but because the claim was specifically limited to and commensurate in scope with the result.
Again, as above, claim 1 is not commensurate in scope with the alleged results.
As above, the claims do not require any specific result regarding inhibition of TNF-alpha induced apoptosis (Fig. 1) or inhibition of stimulated NP cell proliferation (Fig. 2).
Furthermore, the claimed evidence only compares exosomes of generic “de-differentiated fibroblasts” (which is a broad term for any fibroblast-derived cell that has reverted to a more generalized or primitive condition, and which includes stem cells) to fibroblasts.
However, as discussed above, as taught by Lim is was known in the art before the effective filing date that exosomes from stem cells could be used to treat disc degeneration. Furthermore, it would have been predictably obvious to generate those stem cells from fibroblasts as taught by Lai (as discussed in depth above). Therefore, in as much as the results are indicative of effects on disc degeneration, the method of Lim as modified by Lai would have these same results.
Additionally, as above, as evidenced by Cheng et al. (Journal of Cellular and Molecular Medicine, first published 08/14/2017, on IDS 07/05/2022, previously cited, see above in double-patenting rejection), it was known in the art that exosomes secreted from MSCs promote inhibition of TNF-α induced nucleus pulposus cell apoptosis and alleviate intervertebral disc degeneration (Results, p265-270; Fig. 2, p267; Fig. 6, p272-273).
Thus, it was specifically known that stem cells specifically (not fibroblasts – which is the compared cell) can be used to promote disc degeneration.
Therefore, claim 1 is analogous to the fact pattern in regards to 1-7 and 9-10 in Clemens where the term “elevated temperatures” encompassed temperatures as low as 60°C where the prior art ion exchange resin was known to perform well, which was affirmed by the Court.
In regards to Applicant’s arguments that the specification and in the Declaration show exosomes from such dedifferentiated fibroblasts provided to mice as a method of treating disc degeneration, it is noted that there is no evidence of treating disc degeneration in either the specification or the declaration as cited by Applicant. Instead, the instant Application only measures TNF-alpha induced apoptosis (Fig. 1) or inhibition of stimulated NP cell proliferation (Fig. 2), while the declaration only measures the effects of dedifferentiated fibroblasts on HUVEC proliferation and MHC I expression in VH+ dedifferentiated fibroblasts.
Furthermore, in regards to the declaration, as above, the cells in Application no. 18/345,022 explicitly “do not express MHC 1”, while in the instant claims, the cells can express this marker (see claim 3). Therefore, the cells are different in these applications.
Applicant argues that Lim does not teach disc degeneration treatment with exosomes from de-differentiated fibroblasts but only uses exosomes from MSCs for restoring homeostasis generally (Remarks, p7).
Continuing, Applicant argues that the gap between Lim’s MSC exosomes and the claimed de-differentiated fibroblast exosomes is significant and that exosomes from different cell types differ in both content and functionality (Remarks, p7, repeated p9, referencing Valencia et al. (2021), on IDS 11/14/2025)).
Applicant argues that this is further shown in the declaration (submitted in co-pending Application no. 18/345,022) wherein cells dedifferentiated with VPA and under hypoxic conditions (VH+) do not express MHC1 (Remarks, p9).
Applicant’s arguments filed 07/21/2026 have been fully considered but are not found persuasive.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
As discussed above, while Lim does not explicitly teach that the MSCs derived from fibroblasts specifically, methods for “de-differentiating” MSCs from fibroblasts are known in the art.
In particular, Lai teaches a method for the efficient generation of induced Oct-4 expressing MSCs from human dermal fibroblasts, which is achieved by adding a cocktail of chemical inhibitors in culture without reprogramming media comprising transcription factors (Title, Abstract, p1; Discussion, p4; Figure 1, p3). Lai also teaches that MSCs are used in hundreds of clinical trials for disease treatments; have much higher clonogenicity compared to fibroblasts; can be passaged multiple times; and can be further differentiated into osteoblasts, adipocytes, and chondrocytes (Abstract, p1).
Therefore, person of ordinary skill in the arts would have been motivated to use de-differentiated fibroblasts because it could provide an alternate source of MSCs for when obtaining them from blood is not possible or practical, and do so in a way that would be less invasive for patients. Furthermore, because Lai teaches explicit methods for de-differentiating cells (MSCs) from fibroblasts without reprogramming media comprising transcription factors (Discussion, p4; Generation of iMSCs, p9); advocates for their use in therapeutic application (p9, last paragraph of Discussion); and Lim and Lai are in the same technical field of deriving MSCs for clinical application, it could have been done with predictable results and a reasonable expectation of success.
In regards to Applicant’s argument that that the gap between Lim’s MSC exosomes and the claimed de-differentiated fibroblast exosomes is significant and that exosomes from different cell types differ in both content and functionality (Remarks, p7), this is an assertion without evidence.
Moreover, the claims are generic and do not require any particular characteristic of the exosomes other than their ability to treat disc degeneration. However, as above, the exosomes of Lim are specifically used for this purpose.
Additionally, as above, as evidenced by Cheng et al. (Journal of Cellular and Molecular Medicine, first published 08/14/2017, on IDS 07/05/2022, previously cited, see above in double-patenting rejection), it was known in the art that exosomes secreted from MSCs promote inhibition of TNF-α induced nucleus pulposus cell apoptosis and alleviate intervertebral disc degeneration (Results, p265-270; Fig. 2, p267; Fig. 6, p272-273).
Therefore, these were the expected effects of using exosomes from cells with primitive characteristics, such as OCT-4 expressing cells.
In regards to the 132 Declaration previously submitted (04/09/2026) in co-pending Application no. 18/345,022 which is noted is a DIV of the instant application), this declaration has not been submitted for consideration in the instant Application. Therefore, if Applicant wishes this declaration considered it should be submitted and made of record in the instant Application.
Moreover, in regards to marker expression, as noted by Applicant, the cells in Application no. 18/345,022 explicitly “do not express MHC 1”. However, in the instant claims, the cells can express this marker (see claim 3). Therefore, the cells are different in these applications.
In regards to the markers expressed in the instant invention as claimed, as discussed above, as discussed above, as taught by Lim, the exosomes express at least the clamed markers CD9 and CD63 (paragraph [0181]) and therefore, have the same characteristics as claimed.
In regards to Lai, Applicant argues that Lai refers to the cells as “induced MSC-like cells” (Lai, Abstract), but does not refer to the cells as MSCs (Remarks, p7, repeated p8-9).
Continuing, in regards to Lai, Applicant argues that Lai teaches a very specific cocktail of transcription factors that are used to generate the iMSCs (Remarks, p7).
Therefore, Applicant argues that the iMSCs (of Lim) are distinguishable from MSCs (citing Fig. 2 of Lai) and therefore, a person of ordinary skill in the art would know that Lai’s cells are not the MSCs in Lim (Remarks, p7).
Applicant's arguments filed 11/14/2025 have been fully considered but they are not persuasive.
In regards to Applicant arguments in regards to the chemical cocktail of Lai, the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981).
Moreover, the claims do not indicate that other reagents are disallowed by the method. Specifically, claim 1 does not describe a method of de-differentiating fibroblasts “consisting” (which is closed-ended) of exposing fibroblasts to VPA and hypoxia. Rather, the claims are generic, and therefore, given their broadest reasonable interpretation consistent with the specification as directed by MPEP 2111, have been interpreted as allowing steps not recited in the claims.
In regards to Applicant’s arguments that the cells of Lai are not MSCs and therefore presumably, that it would not have been predicably obvious to modify the method of Lim to use the cells as taught by Lai, the title of Lai’s disclosure is “Efficient Generation of Chemically Induced Mesenchymal Stem Cells from Human Dermal Fibroblasts” (first page). Therefore, Lai is explicit that these cells are a type of mesenchymal stem cell.
Furthermore, critically, Lai teaches that “Like BMMSCs, iMSCs can differentiate into osteoblasts, adipocytes, and chondrocytes (Fig. 2, Supplementary Figure S7). Moreover, they markedly attenuate the fatality of endotoxin-induced acute lung injury and decrease the amounts of proinflammatory cytokines in the lung in a mouse model (Figs 3 and 4). iMSCs also share similar molecular signatures with BMMSCs (Fig. 1) and fulfill all of the MSC criteria defined by ISCT5, including plastic adherence, multipotency (Fig. 2, Supplementary Figure S7), and marker expressions (Supplementary Figure S6).”
Therefore, because the iMSCs as taught by Lai meet all of the criteria for an MSC, a person of ordinary skill in the art would have recognized that the cells as taught by Lai are a type of MSC.
In regards to Applicant’s citation of Fig. 2 (p4) of Lai, despite Applicant’s assertions, interpreting this figure would conclude that there is no difference between iMSCs and BMMSCs (bone marrow MSCs). According to Fig. 2 iMSCs and BMMSCs have the same staining patterns, and there is no statistical difference between these groups (see Fig. 2D).
Additionally, it is pointed out that the use of suffix “-like” in reference to cells derived in vitro is commonly employed to distinguish those in vitro-produced cells from primary cells (cells obtained directly from tissues). Thus, a person of ordinary skill in the art would have recognized that the use of the suffix “-like” is used not to imply that the cells are not a type of MSC, but to imply that they are MSCs derived in vitro instead of from primary sources. Indeed, as quoted above, Lai directly compares the iMSCs to BMMCS (bone marrow MCS), a primary, tissue derived MSC.
Therefore, as above, a person of ordinary skill in the arts would have been motivated to use de-differentiated fibroblasts because it could provide an alternate source of MSCs for when obtaining them from blood is not possible or practical, and do so in a way that would be less invasive for patients. Furthermore, because Lai teaches explicit , methods for de-differentiating cells (MSCs) from fibroblasts without reprogramming media comprising transcription factors (Discussion, p4; Generation of iMSCs, p9); advocates for their use in therapeutic application (p9, last paragraph of Discussion); and Lim and Lai are in the same technical field of deriving MSCs for clinical application, it could have been done with predictable results and a reasonable expectation of success.
Moreover, even assuming arguendo that the “mesenchymal stem cell-like cells” as taught by Lai are not a type of MSC, Applicant’s arguments would still be unpersuasive.
As discussed above, as taught by Lai, the iMSCs fulfill all the criteria for an MSC and can differentiate into at least chondrocytes, which as evidenced by the instant specification are well-known to be involved in intervertebral disc organization (see paragraph [0003], “It is well known that the intervertebral discs are made of highly organized matrices of collagen, water, and proteoglycans. Proteoglycan production in the discs is believed to occur by differentiated chondrocytes”).
Therefore, even if arguendo iMSCs are not a type of MSC specifically as argued by Applicant, it is still concluded that it would have been a simple substitution of one known element for another, to modify the method of Lim and use the iMSCs as taught by Lai, with predictable results and a reasonable expectation of success.
Applicant argues that Anokye-Danso does not teach the use of VPA in the context of generating de-differentiated fibroblasts for disc degeneration, but instead uses VPA together with miR302/367 lentiviral transduction to reprogram mouse fibroblasts to fully pluripotent stem cells (Remarks, p7-8).
Applicant argues that critically, Anokye-Danso itself teaches that VPA was not required for reprogramming of human fibroblasts, which undermines any suggestion that VPA would be routinely applied to human fibroblasts for de-differentiation purposes (Remarks, p8).
Continuing, Applicant argues that Anokye-Danso does not teach hypoxic conditions, and therefore, concludes that a person of ordinary skill in the art would not combine the teachings of Anokye-Danso with Lai and Lim (Remarks, p8).
Applicant's arguments filed 11/14/2025 have been fully considered but they are not persuasive.
In regards to other methods taught by Anokye-Danso, the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981).
In regards to Applicant’s arguments that VPA would be routinely applied to human fibroblasts for de-differentiation purposes, it is noted that the claims are generic and not drawn to any specific species.
Thus, in regards to Applicant arguments in regards to the chemical cocktail of Lai, the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981).
Additionally, there is no directive under the analysis of obviousness under 35 USC 103 that a modification be routinely applied, only that the feature was known in the prior art, that there was a motivation to make the modification, and that a person of ordinary skill in the art could have made the modification with predictable results and a reasonable expectation of success (see MPEP 2143).
As discussed above, a person of ordinary skill in the arts would have been motivated to de-differentiate fibroblasts with VPA because Anokye-Danso teaches that VPA is required for reprogramming fibroblasts by specifically degrading Hdac2 which allows for highly efficient reprogramming without expression of other known reprogramming factors (Introduction, p376; as stated by Anokye-Danso, “We also show that valproic acid (VPA) is required for reprogramming mouse fibroblasts by specifically degrading Hdac2 protein, a finding that is supported by the efficient reprogramming of Hdac2 -/- fibroblasts in the absence of VPA). Furthermore, because Anokye-Danso teaches method for reprogramming fibroblasts with VPA (Figure 1, p377), and Lai, Lim, Mathieu, and Anokye-Danso are in the same technical field of utilizing OCT-4 positive cells, it could have been done with predictable results and a reasonable expectation of success.
In regards to Applicant’s arguments that Anokye-Danso does not teach hypoxic conditions, in response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
As discussed above, a person of ordinary skill in the arts would have been motivated to de-differentiate fibroblasts in hypoxic conditions because Mathieu teaches that pluripotent stem cells (OCT-4 expressing cells) have distinct metabolic requirements, and reprogramming cells to pluripotency requires a shift from oxidative to glycolytic metabolism (Summary, p592). Moreover, in particular, Mathieu teaches that reprogramming is significantly more efficient under hypoxic (2% and 5%, which lies within the ranges as in claim 13) conditions (Reprogramming process has hypoxic expression signature, p593). Furthermore, because Mathieu teaches methods for reprogramming fibroblasts under hypoxic (2% and 5%) conditions (Reprogramming process has hypoxic expression signature, p593; Cell culture and reprogramming, p602); and Lim, Lai, and Mathieu are in the same technical field of utilizing OCT-4 positive cells, it could have been done with predictable results and a reasonable expectation of success.
Applicant argues that Matthieu uses hypoxia to enhance reprogramming efficiency in the context of iPSC generation using reprogramming factors (Remarks, p8). Applicant argues that hypoxia is used specifically to promote a metabolic switch from oxidative to glycolytic metabolism, which is a fundamentally different process from the de-differentiation of fibroblasts with VPA and hypoxia as claimed (Remarks, p8).
Applicant argues that there is no teaching in Matthieu that hypoxia would be combined with VPA in the absence of transcription factors to produce de-differentiated fibroblasts whose conditioned media is useful for dis degeneration (Remarks, p8).
Applicant’s arguments filed 07/21/2026 have been fully considered but are not found persuasive.
In regards to other methods taught by Matthieu, the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981).
In regards to Applicant’s argument that the use of Matthieu is fundamentally different from the process as claimed, it is noted that the claims are generic, and no specific result is achieved beyond merely de-differentiating cells.
Furthermore, the fact that the inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985).
As discussed above, a person of ordinary skill in the art would have been motivated to culture fibroblasts under hypoxic conditions because as taught by Matthieu it promotes reprogramming efficiency. Furthermore, since Matthieu uses hypoxia to enhance reprogramming efficiency (and it is noted of fibroblasts), the method of Matthieu achieves the same effect as claimed – the dedifferentiation of fibroblasts.
In regards to Applicant’s arguments that that there is no teaching in Matthieu that hypoxia would be combined with VPA in the absence of transcription factors, in response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e. reprogramming in the absence of transcription factors) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Applicant argues that the Office Action does not articulate why a POSITA would combine both VPA and hypoxia in the specific context of de-differentiating fibroblasts for disc degeneration (Remarks, p8-9).
Relatedly, Applicant argues that there is no articulated reason why a POSITA would look at all four references simultaneously, given their distinct goals, and argues that the combination could not have been made without hindsight bias (Remarks, p9-10).
Applicant’s arguments filed 07/21/2026 have been fully considered but are not found persuasive.
There is no directive under the analysis of obviousness under 35 USC 103 that the modifications be performed at the same time and in the same context (hence the difference in anticipation under 35 USC 102 and obviousness under 35 USC 103). Rather, the analysis is that a feature was known in the prior art, that there was a motivation to make the modification, and that a person of ordinary skill in the art could have made the modification with predictable results and a reasonable expectation of success (see MPEP 2143).
Indeed, in regards to combining references, In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, it would have been predicably obvious to de-differentiate fibroblasts based on the teachings if the prior art as discussed above. Specifically, as taught by Anokye-Danso it was known that VPA is required for reprogramming fibroblasts by specifically degrading Hdac2 which allows for highly efficient reprogramming without expression of other known reprogramming factors. Furthermore, as taught by Matthieu it was known that hypoxic conditions promote reprogramming of fibroblasts to stem cells.
In regards to Applicant’s allegations of hindsight bias, In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Applicant argues that neither Collas or Jung cures the deficiencies of Lim etc. (Remarks, p10).
Applicant’s arguments filed 07/21/2026 have been fully considered but are not persuasive because Lim etc. is not deficient for the reasons discussed above.
Applicant argues that the double-patenting rejections should be withdrawn because the instant Application is the earlier filed application (Remarks, p11).
Applicant’s arguments filed 07/21/2026 have been fully considered but are not found persuasive. The claims are still prima facie obvious as discussed above, and therefore, the non-statutory double patenting rejections have been maintained.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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